Regulatory T-cell therapy: is it ready for the clinic?

The identification of suppressor T cells as important regulators of basic processes that are designed to maintain tolerance has opened an important area of potential clinical investigation in autoimmunity, graft-versus-host disease and transplantation. However, the field has been limited by an inability to define the antigenic specificities of these cells and by the small numbers of circulating regulatory T cells. Recently, new methods for expanding polyclonal and antigen-specific regulatory T cells have emerged. This article summarizes efforts to exploit regulatory T-cell therapy for the treatment of immunological diseases and poses the question of when and where regulatory T cells will first impact on clinical diseases.     

Changing T-cell enigma: Cancer killing or cancer control?

Data from different laboratories and theoretical considerations challenge our current view on anticancer immunity. Immune cells are capable of destroying cancer cells under in vitro and in vivo conditions. Therefore, cellular immunity is considered to control cancers through mechanisms that kill cancers. Yet, therapeutic anticancer immune responses rarely delete cancers. If efficient, they rather establish a life with stable disease. This raises the question of whether killing is the sole mechanism by which immune therapy attacks cancers. Here, we show that, besides cancer eradication by cytotoxic lymphocytes, other modes of action are operative and strictly required for cancer control. We show that T helper-1 cells arrest cancer growth by driving cancers into a state of stable or permanent growth arrest, called senescence. Such immune cells establish cytokine-producing walls around developing cancers. When producing interferon-γ and tumor necrosis factor, this cytokine-induced tumor immune-surveillance keeps the cancer cells in a permanently non-proliferating state. Simultaneously, antiangiogenic chemokines cut their connections to the surrounding tissues. This strategy significantly reduces tumor burden and prolongs life of cancer-bearing animals. As human cancers also undergo senescence, the current data suggest tumor-immune surveillance through cytokine-induced senescence, instead of tumor eradication, as the more realistic and primary goal of cancer control.     

T-cell responses to the trypanosome variant surface glycoprotein: a new paradigm?

During the past decade, extensive knowledge has been gained with respect to the cellular and molecular mechanisms associated with variant surface glycoprotein (VSG) gene switching in trypanosomes. However, comparatively little is known about the cellular and molecular factors that regulate the host B-cell response to VSG determinants during infection. Here, John Mansfield reflects on the nature of this response.     

Naïve to memory T-cell differentiation during homeostasis-driven proliferation

During homeostasis-driven T-cell proliferation, na?ve T cells stably acquire the cell surface markers and functional properties of antigen-induced memory T cells. Thus, in T-cell-deficient individuals, homeostasis-driven T-cell proliferation appears to restore only the memory T-cell compartment, whereas the reconstitution of the na?ve T-cell compartment depends on de novo T-cell development in the thymus.     

Will telomere erosion lead to a loss of T-cell memory?

Evidence is accumulating that elderly individuals are more susceptible to infection with organisms to which they were previously immune. This indicates that there might be a limit to the persistence of immune memory. This fact is particularly disturbing because the average life expectancy of humans has almost doubled in the past 200 years and is still increasing. We discuss mechanisms that might constrain the persistence of memory T cells and consider whether humans will suffer from memory T-cell exhaustion as life expectancy increases.     

Does a facultative precocious life cycle predispose the marine trematode Proctoeces cf. lintoni to inbreeding and genetic differentiation among host species?

Intraspecific variability in parasite life cycle complexity (number of hosts and species of hosts in the life cycle) may have an impact how parasite genetic variation is partitioned among individual parasites, host individuals or host species within a given area. Among digenean trematodes, a three-host life cycle is common. However, a few species are precocious and may reach sexual maturity in what is typically regarded as the second intermediate host. The objective of this study was to determine whether a precocious life cycle predisposes digeneans to possible inbreeding or genetic subdivision among host species. As a study system, we used the digenean Proctoeces cf. lintoni whose metacercariae precociously mature (facultative) without a cyst wall in the gonads of multiple sympatric species of keyhole limpets (Fissurella spp.), typically regarded as the second intermediate hosts. Genotyped parasites were collected from four species of limpets and the clingfish Sicyases sanguineus, the third and final host where sexual maturity occurs. We found very high microsatellite diversity, Hardy–Weinberg equilibrium over all genotyped individuals, and little to no genetic structuring among parasites collected from the different host species. The fact that metacercariae do not encyst in the keyhole limpets, coupled with the high mixing potential of an aquatic environment, likely promote panmixia in local populations of P. cf. lintoni.     

Notch signaling: a rheostat regulating oligodendrocyte differentiation?

Recent studies suggest that Notch signaling provides both instructive and inhibitory cues for oligodendroglial differentiation, depending on the developmental stage and the stimulatory ligand. In the October 17 issue of Cell, Hu et al. present the axonal cell adhesion molecule contactin as a functional Notch ligand, and suggest interesting potential roles for axoglial interactions in regulating oligodendroglial maturation.     

Human T-cell responses to malaria: mostly forgotten or committed to memory?

T cells have been implicated in both malaria immunity and malaria disease and factors controlling the maintenance of T-cell responses over time may alter the clinical outcome o f infection. Michael Good and Janine Bilsborough have compared the T-cell responses to epitopes from the Plasmodium vivax and P. falciparum circumsporozoite proteins and here discuss the issue of T-cell memory as it applies to malaria.     

Vaccination of dogs against Echinococcus granulosus: a means to control hydatid disease?

Hydatid disease continues to be a substantial cause of morbidity and mortality worldwide. Elimination is difficult with current control options, but reducing egg production by Echinococcus granulosus (Eg) in canines might help to reduce transmission in areas where the parasite is endemic. Recently obtained data using recombinant protein-based and live attenuated Salmonella vaccines are preliminary but encouraging and auger well for the future development of an effective dog vaccine against Eg, although much additional work is required before this becomes a reality. New approaches to control and for the prevention of hydatidosis have been described recently, and important additional gains should be expected if the efficacy of the dog vaccines is confirmed and leads to their incorporation into future control options.     

Blocking autophagy to prevent parasite differentiation: a possible new strategy for fighting parasitic infections?

The genome of Trypanosoma cruzi was surveyed for autophagy-related genes. We have identified all the essential genes except for the Atg12 conjugation system and demonstrated functionality of the putative ATG4 and ATG8 homologs. TcAtg4.1 was primarily involved in the proteolytic processing of TcAtg8.1, the ATG8-homolog that was found to be localized to autophagosomal membranes during starvation. Autophagy was also found to be strongly upregulated during differentiation between developmental stages, a process that is essential for the propagation of the parasite. Based on our work, new strategies for treatment of Chagas disease, a chronic debilitating condition still without suitable chemotherapy, can be envisioned.     

Transgenic mosquitoes: a future vector control strategy?

Transgenic mosquitoes may provide a new way of dealing with the old problem of diseases transmitted by insects. Although many technical, and perhaps ethical, problems associated with the wild-release of transgenic insects have yet to be overcome, Julian Crampton and colleagues explore the potential of this technology in the continuing battle to control insect-borne disease.     

Nutritional regulation of JH synthesis: a mechanism to control reproductive maturation in mosquitoes?

Juvenile hormone (JH) titers must be modulated to permit the normal progress of development and reproduction in mosquitoes. In adult female Aedes aegypti, JH levels are low at adult eclosion, elevated in sugar-fed females and low again after a blood meal. Although degradation plays a role, JH titer is fundamentally determined by the rate of biosynthesis in the corpora allata gland (CA). CA from newly eclosed females (0-1 h after emergence) exhibit a very low basal JH biosynthetic activity, Aedes-allatotropin stimulates the CA in newly emerged females to produce JH. There is a correlation between nutritional reserves at adult emergence (teneral reserves) and CA activity. JH synthesis is significantly reduced in teneral females that emerge with low nutritional reserves. Taking a blood meal results in a reduction of CA activity. The biosynthetic activity of Ae. aegypti CA is significantly inhibited by factors present in the head, as well as by Anopheles gambiae PISCF-allatostatin. Nutritional signals affect the release of allatotropin and allatostatins by the brain resulting in the activation or inhibition of JH synthesis. JH is therefore an important part of a transduction mechanism that connects changes in the nutritional status with activation of specific physiological events during reproduction.     

Regulatory T cells: friend or foe in immunity to infection?

Homeostasis in the immune system depends on a balance between the responses that control infection and tumour growth and the reciprocal responses that prevent inflammation and autoimmune diseases. It is now recognized that regulatory T cells have a crucial role in suppressing immune responses to self-antigens and in preventing autoimmune diseases. Evidence is also emerging that regulatory T cells control immune responses to bacteria, viruses, parasites and fungi. This article explores the possibility that regulatory T cells can be both beneficial to the host, through limiting the immunopathology associated with anti-pathogen immune responses, and beneficial to the pathogen, through subversion of the protective immune responses of the host.